title: Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.
abstract: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.
authors.affiliation: 1 Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, and.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.forename: Jacob
authors.initials: J
authors.lastname: Chabon
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Ewa
authors.initials: E
authors.lastname: Kolosionek
authors.forename: Liya
authors.initials: L
authors.lastname: Gebreab
authors.forename: Elias
authors.initials: E
authors.lastname: Debella
authors.forename: Michael
authors.initials: M
authors.lastname: Edwards
authors.forename: Katrina
authors.initials: K
authors.lastname: Diener
authors.forename: Ted
authors.initials: T
authors.lastname: Shade
authors.forename: Gao
authors.initials: G
authors.lastname: Bifeng
authors.forename: Angela
authors.initials: A
authors.lastname: Bandeira
authors.forename: Ghazwan
authors.initials: G
authors.lastname: Butrous
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Geraci
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D020869:Gene Expression Profiling; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012550:Schistosoma mansoni / Q000472:pathogenicity*; D012555:Schistosomiasis mansoni / Q000150:complications; D015398:Signal Transduction
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse